Polycythemia Vera ( PV) is the most common myeloproliterative disorder. PV is believed to arise from a somatic change of a single hematopoietic stem cell, but both the diagnosis and therapy of PV are controversial as its molecular defect or defects have not been characterized. We conclude that JAK2 V617F is not the cause of clonal proliferation of PV but is preceded by other somatic and germ line mutation(s). Thus we hypothesize that besides the JAK2 V617F mutation, additional genetic events are needed for the development of the full PV phenotype;identification of these is the principal goal of this application. These studies will require the combination and integration of data from several genomics approaches. Based on these considerations we plan to pursue three Specific Aims to accomplish our goal: SA 1. Identification of pre-JAK2 somatic mutations causing clonal hematopoiesis by integration of these complementary approaches: SA 1a. Identification of positional candidates through familial co-segregation of genomic regions with the PV phenotype. SA 1 b. Comparison of clonal and polyclonal cells from individual patients with sporadic PV. SA 1c. Identification of shared regions of genome architecture using the Trio family approach for determination of a predisposing inherited haplotype. SA 1d. The candidate genomic regions will be evaluated in detail by whole exonic genome sequencing and entire whole genome sequencing, as this technology is rapidly advancing and its costs are becoming affordable. Our University is acquiring Pacific biosciences platform capable of analyzing 10kb sequence per run by effort spearheaded by this project co-investigator Dr. Jorde. SA 2. Search for nonconventional genetic lesions;i.e. miRNA. In collaboration with Dr. Croce, we will focus on the region of chromosome 6 as a potential germ-line or acquired contributor to the genesis of PV. SA 3. Determine the sequential genomic changes in PV treated by pegylated interferon a in those patients with decreasing JAK2 V617F allelic burden and return of polyclonal hematopoiesis.